Interaction Cross Talk of the Different Signal Transduction Systems

Cellular responses to external stimuli involve an integration of inputs from hormones, neurotransmitters, and growth factors. This integration is able to interact with distinct second messengers. The effect of one signal transduction system may alter the response of another, as already mentioned. This is called cross-talk. Although TSH stimulates both the AC system and the phosphoinositide turnover-calcium systems in animal cell cultures and human neoplastic membranes,43'106 the response patterns of protein phosphorylation to TSH and TPA are different and not reproduced by elevating cAMP by IB MX.194 TSH and TPA had no additive effect on the proliferation of dog thyroid cells.195'196 TPA, however, reduced the cAMP response to TSH when both agonists were incubated in dog and pig thyroid cells.197 199 TSH decreased cAMP-dependent PKA activity in dog thyroid cells,200 but the simultaneous presence of TPA and TSH, in contrast, inhibited TSH-induced downregulation of PKA I.197 TPA had a bipha-sic effect on TSH-induced stimulation of cAMP production in pig thyrocytes.198 TPA potentiated the effect of TSH when pig thyroid cells were exposed simultaneously to TSH and TPA for 10 minutes, but after 20 minutes TPA inhibited the cAMP response to TSH.198 TPA blocked the TSH effect and prevented cAMP-dependent PKA activity.198

Graves' disease IgG can increase PLC activity as well as cAMP production in rat FRTL-5 thyroid cells. PKC modulates different signal transduction systems, leading to positive or negative cross-talk with calmodulin kinase.201 Increased activation of calmodulin kinase by PKC results from PKC-mediated phosphorylation of calmodulin-binding proteins.202 Studies demonstrated that when neoplastic thyroid cells are coincubated with TPA and TSH for 4 hours or longer, TPA decreased the cAMP response compared with that when cells are stimulated with TSH alone.187 This effect of TPA is abolished by coincubation with staurosporine.187

Although EGF does not change the level of cAMP directly, TSH increases cAMP levels, which then stimulates the production of EGF-Rs.153 154 TSH induces proliferation and differentiation expression in dog thyroid cells, whereas EGF and TPA induce proliferation and dedifferentiation. When dog thyrocytes were simultaneously exposed to both TSH and EGF, the expression of protooncogenes, such as c-myc, was lower than with exposure to either EGF or TSH alone.203 Pretreatment with TSH or forskolin increases the response of pig thyroid cells to EGF, probably because of increasing numbers of EGF receptors.154 TSH increases both thyroid cell growth and differentiation, whereas EGF increases only thyroid cell growth and inhibits cell differentiation. EGF also inhibits TSH-mediated thyroglobulin synthesis, morphologic differentiation, and iodide uptake, as well as organification.144'204"206 In general the PKC- and PTK-mediated pathways are triggered by TPA and EGF.207 Increased concentrations of intracellular cAMP block activation of raf-1 and MAPK in fibroblasts.132 Thus, EGF-dependent MAPK activation was blocked by forskolin or IBMX. PKA probably phosphorylates and inactivates MAPKs. Dibutyryl cAMP blocks DNA synthesis and also signal transmission from ras by inhibiting raf activation.132 The incubation of EGF and TSH together induced a significant decrease in cAMP response to TSH compared with the cAMP response that resulted after stimulation with TSH alone.190 Thus, EGF inhibits TSH-stimulated cAMP production. The inhibition of cAMP was abolished when neoplastic thyroid cells were incubated with TSH, EGF, and EGF-R-monoclonal antibody 528.190

Natriuretic peptides (NPs) and their receptors (NP-R) have been identified in thyroid gland.208 Although atrial natriuretic factor inhibits cAMP formation and thyroglobulin production in primary thyrocyte cultures through subsequent activation of Gi NAPs, binding to NP-R can activate AC.209

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